The present invention relates to a method for producing efficiently optically active endo-2-norborneols useful as synthetic intermediates of pharmaceutical preparations and the like.
In recent years, it has been earnestly required to synthesize physiological active materials of pharmaceutical preparations as optically active compounds. When these materials have optical isomers, several isomers have different active properties. One isomer exhibits strong activity and the other isomer exhibits little activity or exhibits undesirable toxicity. When physiologically active materials are synthesized for pharmaceutical preparations, therefore, it is desired to selectively prepare optical isomers having preferable steric configuration in view of a fully developed physiological activity and safety.
Hitherto, to obtain optically active endo-2-norborneols, the following methods have been reported: (1) a method for optically resolving racemic endo-2-norborneols by a diastereomer method (Winstein et al., J. Am. Chem. Soc., 74, 1147 (1952)), (2) a method for optically resolving racemic 2-norbornanone with a microorganism by stereoselective reduction (Nakazaki et al., J. Org. Chem., 45, 4432 (1980) ), (3) a method for stereoselectively reducing racemic 2-norbornanone with alcohol dehydrogenase of horse liver (Jones et al., J. Am. Chem. Soc., 98, 8476 (1976)), (4) a method for stereoselectively acylating racemic endo-2-norborneol in the presence of lipase of pig spleen (Saccomano et al., Tetrahedron Lett., 33, 1201 (1992)), (5) a method of stereoselective transesterification of racemic endo-2-acetoxynorbornane in the presence of the lipase derived from Candida cylindracea (Macfarlane et al., J. Chem. Soc. Perkin. Trans., 1, 2287 (1993)), (6) a method for stereoselectively acylating racemic-endo-2-norborneol in the presence of lipase derived from Pseudomonas (Naemura et al., Bull. Chem. Soc. Jpn., 66, 573 (1993) ), (7) a method for stereoselectively hydrolyzing racemic endo-2-acetoxynorbornane in the presence of the lipase derived from Candida cylindracea (Brackenridge et al., J. Chem. Soc. Perkin. Trans., 1, 1093 (1993) and the like.
The method of (1) however is not efficient because recrystallization should be repeated to increase the optical purities of the resulting compounds. In the method of (2), further, it is difficult to obtain strains to be used and the substrate concentration is very low against much charge stock (0.075 w/v %). The method of (3) is impractical because it is difficult to obtain alcohol dehydrogenase and NAD of a coenzyme, and the yield is low in the asymmetric reaction. In the method of (4), a side reaction easily occurs and the water content of the reaction system should be decreased precisely to prevent the side reaction. Since the enzyme should be added several times during the reaction, the operation is very troublesome. The method is industrially disadvantageous because diethylether, which is very flammable as a reaction solvent, should be used. In the method of (5), it is difficult to obtain the ester of starting materials and the low optical purity of the product is insufficiently 32% ee. In the method of (6), the optical purity of the product is also very low and it is 63%. The water content of the reaction system should be decreased to prevent the side reaction. The stability of isopropenyl acetate of an acylation agent is not enough and it is difficult to obtain the compound in large quantities. Although the method of (7) is very close to the method of the present invention, it does not disclose enough the reaction conditions and the optical purity of the product is very low 60% ee.
These conventional methods have been not perfect in practical use at the industrial level.